: The dysregulation of developmental and stem cell associated genes is a common phenomenon during cancer development. Around half of acute myeloid leukemia (AML) patients express high levels of HOXA cluster genes and MEIS1. Most of these AML cases harbor an NPM1 mutation (NPM1c), which encodes for an oncogene mislocalized from the nucleolus to the cytoplasm. How NPM1c expression in hematopoietic cells leads to its characteristic gene expression pattern remains unclear. Here, we show that NPM1c directly binds to specific chromatin targets, which are co-occupied by the histone methyltransferase KMT2A (MLL1). Targeted degradation of NPM1c leads to a rapid decrease in gene expression and loss of RNA Polymerase II, as well as activating histone modifications at its targets. We demonstrate that NPM1c directly regulates oncogenic gene expression in collaboration with the MLL1 complex and define the mechanism by which MLL1-Menin small molecule inhibitors produce clinical responses in patients with NPM1-mutated AML.

Mutant NPM1 directly regulates oncogenic transcription in acute myeloid leukemia / Uckelmann, Hannah J; Haarer, Elena L; Takeda, Reina; Wong, Eric M; Hatton, Charlie; Marinaccio, Christian; Perner, Florian; Rajput, Masooma; Antonissen, Noa J C; Wen, Yanhe; Yang, Lu; Brunetti, Lorenzo; Chen, Chun-Wei; Armstrong, Scott A. - In: CANCER DISCOVERY. - ISSN 2159-8290. - (2022). [10.1158/2159-8290.CD-22-0366]

Mutant NPM1 directly regulates oncogenic transcription in acute myeloid leukemia

Brunetti, Lorenzo;
2022-01-01

Abstract

: The dysregulation of developmental and stem cell associated genes is a common phenomenon during cancer development. Around half of acute myeloid leukemia (AML) patients express high levels of HOXA cluster genes and MEIS1. Most of these AML cases harbor an NPM1 mutation (NPM1c), which encodes for an oncogene mislocalized from the nucleolus to the cytoplasm. How NPM1c expression in hematopoietic cells leads to its characteristic gene expression pattern remains unclear. Here, we show that NPM1c directly binds to specific chromatin targets, which are co-occupied by the histone methyltransferase KMT2A (MLL1). Targeted degradation of NPM1c leads to a rapid decrease in gene expression and loss of RNA Polymerase II, as well as activating histone modifications at its targets. We demonstrate that NPM1c directly regulates oncogenic gene expression in collaboration with the MLL1 complex and define the mechanism by which MLL1-Menin small molecule inhibitors produce clinical responses in patients with NPM1-mutated AML.
2022
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11566/309688
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